{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRMU is a nuclear‐encoded, highly conserved mitochondrial enzyme that catalyzes the 2‑thiolation of the wobble uridine (U34) in specific mitochondrial tRNAs (including tRNA^Lys, tRNA^Glu, and tRNA^Gln), a modification essential for accurate and efficient mitochondrial protein synthesis. This tRNA modification ensures proper codon recognition during translation and is vital for mitochondrial respiratory chain function. In model systems ranging from yeast to mice and humans, TRMU has been shown to localize to mitochondria and to function analogously to its bacterial homologs, underscoring its evolutionary conservation and central role in mitochondrial gene expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in tRNA modification, TRMU also acts as a nuclear modifier gene that modulates the phenotypic expression of mitochondrial DNA mutations. For example, in patients carrying pathogenic 12S rRNA mutations associated with aminoglycoside‐induced and nonsyndromic deafness, the presence of TRMU mutations (such as the A10S missense change) exacerbates mitochondrial dysfunction, leading to impaired mitochondrial tRNA metabolism and reduced mitochondrial protein synthesis. In some reports, insufficient TRMU activity—potentially compounded by transient limitations in substrates like cysteine during neonatal development—has been linked to severe outcomes such as acute infantile liver failure. Moreover, regulatory mechanisms such as microRNA‑mediated down‐regulation of TRMU under oxidative stress further tie its function to the broader landscape of mitochondrial and metabolic pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, the studies demonstrate that TRMU is central not only to mitochondrial translation via its role in tRNA modification but also to the modulation of mitochondrial disease phenotypes. Its dysfunction—whether through genetic mutations that alter its enzymatic stability or through regulatory pathways affecting its expression—results in decreased 2‑thiolation of mitochondrial tRNAs, impaired mitochondrial protein synthesis, and consequent respiratory deficiencies. These defects have been implicated in a variety of clinical presentations, including sensorineural deafness, liver failure, and other mitochondrial disorders. Importantly, emerging therapeutic strategies, such as cysteine or N‑acetylcysteine supplementation to support thiolation reactions, underscore the translational relevance of understanding TRMU’s function in health and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qingfeng Yan, Min-Xin Guan "}, {"type": "b", "children": [{"type": "t", "text": "Identification and characterization of mouse TRMU gene encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbaexp.2003.11.010"}], "href": "https://doi.org/10.1016/j.bbaexp.2003.11.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14746906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14746906"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Noriko Umeda, Takeo Suzuki, Masashi Yukawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondria-specific RNA-modifying enzymes responsible for the biosynthesis of the wobble base in mitochondrial tRNAs. Implications for the molecular pathogenesis of human mitochondrial diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M409306200"}], "href": "https://doi.org/10.1074/jbc.M409306200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15509579"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15509579"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Qingfeng Yan, Xiaoming Li, Gèrard Faye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in MTO2 related to tRNA modification impair mitochondrial gene expression and protein synthesis in the presence of a paromomycin resistance mutation in mitochondrial 15 S rRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M504247200"}], "href": "https://doi.org/10.1074/jbc.M504247200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15944150"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15944150"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Qingfeng Yan, Yelena Bykhovskaya, Ronghua Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2006.02.078"}], "href": "https://doi.org/10.1016/j.bbrc.2006.02.078"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16513084"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16513084"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Min-Xin Guan, Qingfeng Yan, Xiaoming Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/506389"}], "href": "https://doi.org/10.1086/506389"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16826519"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16826519"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "D Otaegui, H Irizar, M Goicoechea, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular characterization of putative modulatory factors in two Spanish families with A1555G deafness."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Audiol Neurootol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000124280"}], "href": "https://doi.org/10.1159/000124280"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18391568"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18391568"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Erwin Reiling, Jana V van Vliet-Ostaptchouk, Esther van 't Riet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic association analysis of 13 nuclear-encoded mitochondrial candidate genes with type II diabetes mellitus: the DAMAGE study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2009.4"}], "href": "https://doi.org/10.1038/ejhg.2009.4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19209188"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19209188"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Vanessa Cristine Sousa de Moraes, Fabiana Alexandrino, Paula Baloni Andrade, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Study of modifiers factors associated to mitochondrial mutations in individuals with hearing impairment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2009.02.014"}], "href": "https://doi.org/10.1016/j.bbrc.2009.02.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19338775"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19338775"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Avraham Zeharia, Avraham Shaag, Orit Pappo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Acute infantile liver failure due to mutations in the TRMU gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2009.08.004"}], "href": "https://doi.org/10.1016/j.ajhg.2009.08.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19732863"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19732863"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Florin Sasarman, Hana Antonicka, Rita Horvath, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The 2-thiouridylase function of the human MTU1 (TRMU) enzyme is dispensable for mitochondrial translation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr397"}], "href": "https://doi.org/10.1093/hmg/ddr397"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21890497"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21890497"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Florin Sasarman, Tamiko Nishimura, Isabelle Thiffault, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.22098"}], "href": "https://doi.org/10.1002/humu.22098"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22504945"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22504945"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Salvador Meseguer, Ana Martínez-Zamora, Elena García-Arumí, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu427"}], "href": "https://doi.org/10.1093/hmg/ddu427"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25149473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25149473"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Feilong Meng, Xiaohui Cang, Yanyan Peng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biochemical Evidence for a Nuclear Modifier Allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) Related to Mitochondrial tRNA Modification in the Phenotypic Manifestation of Deafness-associated 12S rRNA Mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M116.749374"}], "href": "https://doi.org/10.1074/jbc.M116.749374"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28049726"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28049726"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Somayeh Khatami, Hassan Rokni-Zadeh, Neda Mohsen-Pour, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Whole exome sequencing identifies both nuclear and mitochondrial variations in an Iranian family with non-syndromic hearing loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mitochondrion (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mito.2018.08.006"}], "href": "https://doi.org/10.1016/j.mito.2018.08.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30205178"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30205178"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Qiufen He, Qiong Zhao, Qianqian Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mtu1 defects are correlated with reduced osteogenic differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-020-03345-5"}], "href": "https://doi.org/10.1038/s41419-020-03345-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33431792"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33431792"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Chaya N Murali, Claudia Soler-Alfonso, Kathleen M Loomes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2021.01.005"}], "href": "https://doi.org/10.1016/j.ymgme.2021.01.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33485800"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33485800"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Chao Chen, Min-Xin Guan "}, {"type": "b", "children": [{"type": "t", "text": "Genetic correction of TRMU allele restored the mitochondrial dysfunction-induced deficiencies in iPSCs-derived hair cells of hearing-impaired patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddac096"}], "href": "https://doi.org/10.1093/hmg/ddac096"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35467742"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35467742"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Georg F Vogel, Yael Mozer-Glassberg, Yuval E Landau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Med (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gim.2022.09.015"}], "href": "https://doi.org/10.1016/j.gim.2022.09.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36305855"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36305855"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Weimin Ni, Jie Zhang, Bing Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Actin related protein 2/3 complex subunit 1 up-regulation in the hypothalamus prevents high-fat diet induced obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Neurosci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/ejn.15871"}], "href": "https://doi.org/10.1111/ejn.15871"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36382618"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36382618"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Raja Norazireen Raja Ahmad, Long-Teng Zhang, Rikuri Morita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkad1197"}], "href": "https://doi.org/10.1093/nar/gkad1197"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38113276"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38113276"}]}]}]}